There are large individual differences in reactivity to drugs of abuse, but the causes of these differences are not well understood. The recent experience of "stress" is a factor known to potentiate drug reward processes in both humans and animals, but the aspects of stress that are critical and the neural mechanisms involved are not fully known. The proposed research explores the role of the degree of behavioral control that the individual has over the stressor as a feature modulating wither the stressor will alter drug reactivity, and focuses on stressor-induced sensitization of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) as a mediator. The hypothesis to be tested is that 1) uncontrollable (but not controllable) stressors sensitize DRN 5-HT neurons for a period of time, leading to exaggerated release of 5-HT in projection regions when the neurons are activated; 2) 5-HT released in the nucleus accumbens (NAc) and/or medial prefrontal cortex (mPFC) by neurons projecting from the DRN increases the extracellular level of DA in the these regions that is produced by drugs of abuse; 3) 5-HT released in the paraventricular nucleus increases the blood levels of corticosterone (CORT); 4) Drugs that activate DRN 5-HT neurons (e.g., morphine) in addition to acting on brain reward structures, will therefore produce greater levels of extracellular DA in the NAc/mPFC and CORT in blood for subjects that have recently received uncontrollable stressors; 4) uncontrollable (but not controllable) stressors will therefore potentiate behavioral responses to drugs that depend on NAc/mPFC DA and/or CORT, and this potentiation will occur for drugs that activate DRN 5-HT neurons. Conditioned place preference and locomotor activation are the behaviors to be examined, and morphine, amphetamine, heroin, nicotine, cocaine, and ethanol are the drugs that will be tested.